Current and Reports (2019) 19:60 https://doi.org/10.1007/s11882-019-0891-1

FOOD ALLERGY (E KIM, SECTION EDITOR)

Prevention of Non- Food

Elissa M. Abrams1,2 & Edmond S. Chan1,3

# Springer Science+Business Media, LLC, part of Springer Nature 2019

Abstract Purpose of Review The purpose of this review article is to discuss the recent literature around methods of prevention of food allergies other than . Recent Findings While the most robust data to date exists for peanut, there are emerging studies suggesting a beneficial effect to early introduction of cooked egg, and cow’s milk as well. While the literature is sparse for other such as tree nuts, finned fish, and shellfish, the mechanism of sensitization is thought to be the same and no study to date has demonstrated a harm with allergenic introduction in the 4–6 months of age window (nor has there been level 1 evidence of benefit to delay of such allergens). This strategy is safe, and pre-emptive testing is not required prior to allergenic solid introduction. Summary All allergenic solids should be introduced at around 6, but not before 4, months of age in infants at high risk.

Keywords . Allergy prevention . Food introduction . Complementary feeding . Eczema . Primary prevention . Pediatric allergic disease

Prevention of Non-peanut Food Allergies USA, which recommends that infants with the same risk fac- tors as the LEAP study (severe eczema and/or ) be Food allergy is estimated to affect 2–10% of the population, introduced to peanut at 4–6monthsofage[4••]. However, less and there has been an increase in food allergy prevalence over is known about prevention of allergies other than peanut, and time [1]. The US Centers for Disease Control and Prevention less definitive guidance is available. The goal of this review is documented an almost doubling of food allergy prevalence in to discuss prevention of non-peanut food allergies and to re- the USA between 1997 and 2011 (3.4% to 5.1%) [2]. There view what gaps in the literature yet remain. The first section of has been significant focus on the prevention of peanut allergy this review will focus on the studies that have examined early since the publication of the Learning Early About Peanut introduction of allergenic solids other than peanut (such as (LEAP) study, the first randomized controlled trial to demon- egg, cow’s milk, and wheat). Subsequently, the review will strate up to an 80% reduction in peanut allergy with early examine implementation of this research into policy, and peanut ingestion in a high-risk group of infants [3••]. This therein what questions remain. study was largely the impetus for the subsequent release of the National Institute of Allergy and infectious Diseases (NIAID) guideline on the prevention of peanut allergy in the Early Introduction of Allergenic Solids Other than Peanut This article is part of the Topical Collection on Food Allergy There are 8 common allergens that account for over 90% of all * Edmond S. Chan food reactions in children—milk, egg, peanut, tree nuts (al- [email protected] mond, , , , , , Brazil ), 1 Division of Allergy and , Department of Pediatrics, wheat, soy, finned fish, and shellfish [5]. In general, while the Faculty of Medicine, University of British Columbia, preponderance of the literature has been focused on peanut, it Vancouver, British Columbia, Canada is thought that the mechanism of sensitization to allergenic 2 Division of Pediatrics, Section of Allergy and Clinical Immunology, foods is similar, no matter the allergenic solid. This mecha- University of Manitoba, Winnipeg, Manitoba, Canada nism is termed the dual- exposure hypothesis and 3 BC Children’s Hospital Research Institute, Vancouver, British notes that cutaneous exposure to allergens in the absence of Columbia, Canada ingestion increases the risk of food sensitization [6•]. This 60 Page 2 of 9 Curr Allergy Asthma Rep (2019) 19:60 theory is supported by studies noting, for example, that muta- egg allergy with earlier introduction (risk ratio 0.222; 95%CI, tions in the filaggrin (FLG) gene (involved in skin hydration 0.081–0.607; P = 0.0012) [12••]. In fact, the study was so and water retention) have been strongly linked with eczema, successful that it was halted prematurely. and independently with food allergy as well [7–9]. A cohort In contrast, four randomized controlled trials examining study of 13,971 preschool children noted that the use of - early pasteurized raw egg introduction have either not nut oil in infancy was significantly associated with the devel- shown a significant benefit or have noted high rates of ad- opment of peanut allergy among children with eczema (odds verse events with early ingestion of raw egg in infancy. The ratio [OR] 6.8; 95%CI, 1.4–32.9) [10]. Beating Egg Allergy Trial (BEAT) randomized 319 infants with a family history of to freeze-dried whole raw Multiple Allergenic Solids pasteurized egg powder ingestion at 4 months of age or placebo until 8 months of age, with outcome of sensitization There has been one study, Enquiring About Tolerance (EAT), to egg white at 1 year of age. There was a significant re- that randomized 1303 general population infants to early in- duction in egg white sensitization with early egg introduc- troduction of 6 common allergens (peanut, cow’s milk, finned tion (OR 0.46; 95%CI, 0.22–0.95) although there was a non- fish, wheat, egg, sesame) at 3 versus 6 months of age in pre- significant trend in the reduction of egg allergy and a high viously exclusively breast-fed infants [23••]. In the intention rate of reactions with early introduction [13]. The Hen’sEgg to treat analysis, there was no significant difference in the rate Allergy Prevention (HEAP) study randomized 406 infants to of food allergy between the early and standard introduction pasteurized egg white equal in its allergenicity to raw hen’s groups (5.6% vs 7.1% respectively; P = 0.32) although in the egg or placebo from age 4–6 until 12 months of age and per-protocol analysis, there was a significant reduction in food found no significant difference in rate of egg sensitization allergy overall with early introduction (2.4% vs 7.3%; P = (5.6% vs 2.6% respectively, P = 0.24) or allergy (2.1% vs 0. 0.01). In the per-protocol analysis, there was a 75% reduction 6% respectively, P = 0.35) at a year of age and a high rate of in egg allergy (1.4% vs 5.5%; P = 0.009) and 100% reduction reactions on initial exposure to egg [14]. The study was in peanut allergy (0% vs 2.5%; P = 0.003) with early intro- terminated early due to high rates of reactivity noted on duction. Adherence was a significant issue in this study initial egg ingestion and this recruitment termination is a (42.8% overall). Rates of adherence to early ingestion varied, limitation of the study. The Solids Timing for Allergy with higher rates for milk (85.2%), peanut (61.9%), and fish Research (STAR) trial randomized 86 infants with (60.0%) than for sesame (50.7%), or egg (43.1%). moderate-to-severe eczema to pasteurized raw whole egg powder introduction at either 4 months or avoidance until Egg 8 months, with an outcome of egg allergy at a year of age. There was a non-significant trend towards lower rates of egg There has been one observational study and five randomized allergy in the early introduction group compared with those controlled trials examining early egg introduction as a means in the control group (51% relative risk; 95%CI, 0.38–1.11; of allergy prevention. The results of these studies are less P = 0.11) although a high rate of allergic reactions (31%) consistent than for peanut, although it is hypothesized that part was noted with early introduction [15]. The Starting Time of this discrepancy between studies is related to the form (i.e., of Egg Protein (STEP) study randomized 820 infants with a cooked vs baked vs raw) in which egg is introduced. family history of atopy to pasteurized raw whole egg pow- The most successful studies to date have been the der introduction at 4 to 6 months of age or avoidance until HealthNuts population-based observational study and 10 months of age and found a non-significant reduction in PETIT, a randomized study in Japan [11, 12••]. The egg allergy with early introduction (7.0% vs 10.3%; adjusted HealthNuts, a population-based study of 2589 general risk relative risk 0.75; 95%CI, 0.48–1.17) [16]. infants in Melbourne, Australia, noted that introduction of Despite the discrepancy in the literature to date, a recent egg at 4–6 months of age was associated with a lower preva- meta-analysis and of timing of allergenic lence of egg allergy compared with later introduction in both food introduction and risk of allergic disease found that there high risk, which was defined as having a family history of was moderate-certainty evidence (5 trials, 1915 participants) food allergy or a personal history of eczema or reactions to that early egg introduction at 4–6monthsofagewasassoci- other foods (aOR 1.6 for introduction at 10–12 months and 3.4 ated with reduced egg allergy (risk ratio 0.56; 95%CI, 0.36– for introduction after 12 months) and lower risk infants (OR 0.87) [17••]. The means by which egg is introduced (cooked 3.3; 95%CI, 1.1–1.9 at 10–12 months) [11]. In addition, the versus raw) can influence its allergenicity and likely explain PETIT study randomized 147 infants with eczema (of any the discrepancy in results. The HealthNuts study noted that severity as long as it met diagnostic criteria) to introduction first ingestion of cooked egg compared with that of baked egg of heated (cooked) egg powder at 6 months of age or avoid- reduced the risk of egg allergy (OR 0.2; 95%CI, 0.06–0.71) ance until a year and noted a significantly lower rate of cooked [11]. Curr Allergy Asthma Rep (2019) 19:60 Page 3 of 9 60

Cow’s Milk What Should Future Guidelines Recommend for Introduction of Foods Other than Peanut? The studies on early cow’s milk introduction are all observa- tional and all have focused on early, regular (often daily) While there is now specific North American guidance on early cow’s milk ingestion in the first 3 months of life (i.e., cow’s peanut introduction, other guidelines are less clear for allergens milk formula vs breastmilk). The first study of early cow’s other than peanut. For example, the British Society of Allergy and milk introduction, from 2010, was a prospective study of Clinical Immunology (BSACI) counsels that infants who are at 13,019 infants from Israel and noted that regular exposure to higher risk (eczema or food allergy) introduce egg and peanut cow’s milk formula starting within the first 14 days of life was from 4 months of age, but does not comment about earlier intro- associated with a lower risk of cow’s compared duction of other allergenic solids [24]. For lower risk infants, it with later exposure (OR 19.3 for introduction after 14 days of recommends complementary food introduction at “around 6 age) [18]. This study on cow’s milk introduction, in contrast to months of age but not before 4 months of age” and aims to the early egg introduction literature, also noted irregularity of include “foods associated with food allergies” (egg, nuts, cow’s exposure to increase the risk of cow’s milk allergy. A case- milk, finned fish, shellfish, wheat) before 12 months of age. The control study of 51 children with diagnosed cow’smilkallergy Australasian Society of Clinical Immunology and Allergy compared with 102 controls and 32 egg allergic children (to (ASCIA) recommends introducing solids at “around 6 months, minimize the effect of confounders) noted early (< 1 month of but not before 4 months” and focuses on peanut and egg intro- age) and regular (> 1/day) cow’s milk ingestion significantly duction in the first year of life [25]. However, the ASCIA also has reduced the risk of cow’s milk allergy [19]. Of note, this study advice for parents that other common allergy-causing foods such also found irregular cow’s milk exposure to increase risk. as cow’s milk (dairy), tree nuts, soy, sesame, wheat, fish, and other Finally, a recent analysis of the HealthNuts data noted that seafood be introduced by 12 months. The Canadian Pediatric early exposure to cow’s milk within the first 3 months of life Society (CPS) also focuses on “around 6 months, but not before was associated with a reduced risk of cow’s milk allergy (aOR 4months” for introduction of allergenic solids in infants at higher 0.31; 95%CI, 0.10–0.91) at a year of age [20]. risk (eczema, food allergy, or immediate family history of atopy) While the literature to date with cow’s milk ingestion is and, while not limited to egg or peanut, notes the evidence is observational, there is certainly an association between early strongest for early introduction of these two allergens [26]. cow’s milk ingestion and lower rates of cow’smilkallergy.A While many guidelines also emphasize early egg introduction, randomized trial of cow’s milk formula versus breastmilk sis there is a dilemma about how to counsel families about introduc- unlikely due to ethical considerations and any benefit of early tion of other allergens such as cow’s milk, tree nuts, wheat, cow’s milk ingestion in the first few months of life must be finned fish, and shellfish. There are benefits to focusing on only balanced against the many known benefits to mother and child peanut and egg—the message is simple, there is good evidence from exclusive breastfeeding [21]. of benefit, and for peanut the risk of lifelong allergy is high. However, there are benefits to including all the “common 8” allergens in guidance on early introduction—the mechanism of Wheat sensitization (and hence protection) is likely the same, it is un- likely for clinical trials like LEAP and PETIT to be repeated for There is one observational study looking at early wheat intro- all allergenic foods, and it removes variability in approach. duction. A cohort of 1612 children who were enrolled at birth However, this recommendation would be admittedly less evi- and followed into toddlerhood noted that children who were dence-based, and a take-home lesson from EAT is that adherence first ingesting wheat cereal before 6 months of age had a lower to early introduction of multiple allergenic solids is difficult. risk of than those who started ingesting wheat In the authors’ opinion, a simpler message for future guide- cereal after 6 months of age (OR 4.77; 95%CI, 1.33–17.09) lines may be that parents should introduce high-risk infants to [22]. There have been no randomized trials on early grain all allergenic solids early “at around 6 months but not before ingestion to date. However, grains are a commonly introduced 4months” of age. The issue of pre-emptive screening will be early solid especially in higher income countries where infant discussed later in this review. This could be based on extrap- grain cereals are iron-fortified. olating the evidence from peanut and cooked egg to other allergenic foods, as well as the absence of level 1 evidence for benefit to intentionally delaying the introduction of any Tree Nuts, Soy, Finned Fish, Shellfish allergenic food. This simpler message would allow for region- al variability in prevalence of food allergy (e.g., in countries There are no studies to date specifically examining early in- where seafood allergy is more prevalent, it would permit con- troduction of these allergens alone as a means of allergy sideration of early introduction of seafood). Among the list of prevention. allergenic foods, the foods of highest priority (in sequence) 60 Page 4 of 9 Curr Allergy Asthma Rep (2019) 19:60 appear to be peanut, cooked egg, cow’s milk, and tree nuts in be as important as age of introduction. This is well illustrated countries like the USA and Canada. For tree nuts, there is for by a case that one of the authors had of a 5-year-old child who example some evidence that cashew allergy is increasing in since the age of a year had ingested cashew about a dozen frequency [27]. This allergy is commonly severe and is rarely times at a frequency of once every 3–4 months. At about age outgrown [28–30]. It has been noted that cashew nut allergen 4 years, he began to have reactions to cashew, which occurred has “high potency” and is a “clearly underestimated important on three separate occasions (, , and public health problem, especially in children” [27]. It has been lethargy). Skin prick testing was highly positive (8 mm) to noted that identifying how to prevent is an cashew. This case suggests that early introduction is not suf- “urgent priority” for future research [31]. As a result, despite ficient for prevention of cashew allergy and that frequency the paucity of literature on early tree nut introduction, the may be equally important, but difficult to implement and authors also tend to counsel families, especially families at quantify. risk, to feed commonly allergenic tree nuts such as cashew However, other than peanut, there is very little guidance and walnut early in life, in an age-appropriate way to prevent available about the frequency, or amount, that is required of choking risk (such as smooth cashew or walnut butter). allergenic solids to maintain tolerance. The EAT study noted that weekly consumption of 4 g of egg protein (2 g of egg white protein) was effective in the prevention of egg allergy Which Infants Will Benefit from Early [23••], but no guidance exists at all for any of the other non- Introduction? peanut allergenic solids. The CPS practice point recommends feeding allergenic As highlighted above, the definitions of high risk used in solids “a few times a week” in keeping with the LEAP proto- guidance vary. Traditionally, until the LEAP study, the defini- col although this recommendation was an expert opinion and tion used in most guidelines on allergy prevention was a first- not evidence-based [26]. The ASCIA and BSACI guidelines degree family history of atopy [32, 33]. This definition is recommend ongoing ingestion but do not specify the amount supported by genome-wide association studies and population or frequency [24, 38]. Practically, it may be simplest to coun- studies as well [34, 35]. sel a family that, once it is in the diet, keep it in the diet as they However, in keeping with the dual-allergen exposure hy- would any other food that is well tolerated and integrate it into pothesis, eczema, and in particular eczema severity, is increas- the family diet as well. However, this remains an area where ingly being recognized as likely the most significant risk fac- further research is required to provide a definitive tor for food allergy development. Results from the HealthNuts recommendation. study note that infants with eczema are 11.0 times more likely to develop peanut allergy (95%CI, 6.6–18.6) and 5.8 times more likely to develop egg allergy (95%CI, 4.6–7.4) than Should Testing Be Done Prior to Introduction infants without eczema [36]. A recent systematic review of of Allergenic Solids Other than Peanut? 66 studies identified a strong and dose-dependent association between eczema, food sensitization, and food allergy [37]. The NIAID guideline recommends that infants at high risk This systematic review also noted evidence that eczema pre- (severe eczema and/or egg allergy) have pre-emptive screen- ceded the development of food allergy, in keeping with the ing prior to peanut introduction [4]. In general, no guideline to dual-allergen exposure hypothesis. date has recommended blanket pre-emptive screening be ini- As a result, the CPS guidance includes infants with a his- tiated to allergenic solids other than peanut. In addition, sig- tory of allergies themselves, such as eczema or other food nificant concerns about the feasibility (including limited avail- allergy, and/or an immediate family history of atopy, as the ability of confirmatory infant oral food challenges), imple- definition of high risk. This broad definition also encompasses mentation, cost-effectiveness, and possibility of a “screening the current thinking that, as noted in the NIAID guideline, the creep” have been raised with pre-emptive peanut testing “mechanisms of protection” are not likely different, especially [39–42]. A Canadian editorial on the NIAID guideline specif- among infants with mild eczema compared with those with ically noted concern that “healthcare providers…may order more severe eczema. testing to foods other than peanut (during the process of test- ing peanut)…” [43]. One common previous exception was testing for tree nut in How Frequently Do Allergenic Foods Need a child with peanut allergy who had not ingested tree nuts, to Be Fed Once Introduced? which was recommended as a possible reason for pre-emptive testing as recently as 2010 as co-allergy was thought to be As noted with the observational studies on early cow’smilk common [44]. It is increasingly recognized that this may be introduction, frequency of ingestion of allergenic solids may in fact cross-sensitization instead of co-allergy. For example, a Curr Allergy Asthma Rep (2019) 19:60 Page 5 of 9 60 study of 324 patients referred for food allergy noted that while prevention [32, 33]. This recommendation was based in part the majority (86%) of patients with peanut allergy were sen- on the results of the prospective German Infant Nutritional sitized to tree nuts, only 34% had documented allergy [45]. A Intervention Study (GINI), which found a reduced risk of recent study of oral food challenge outcomes noted that allergic disease with the use of hydrolyzed formula compared among children with peanut allergy and tree nut co-sensitiza- with that of standard cow’s milk formula for the first 4 months tion, the tree nut oral food challenge passage rate was 96%, of life [49]. Despite this, a Cochrane review noted “limited “questioning the clinical relevance of ‘co-allergy” [46]. evidence” that hydrolyzed formula compared with regular Allergy testing, both skin prick testing (SPT) and specific- cow’s milk formula reduced the risk of infant and childhood IgE (sIgE) testing, has low specificity in the absence of a allergy and cows’ milk allergy [50]. history of a reaction. A retrospective chart review of 125 chil- In addition, a recent meta-analysis of 37 studies (over dren with a history of positive allergy testing noted that 84– 19,000 participants) noted no evidence that partially or exten- 93% of the foods being avoided due to positive allergy tests sively hydrolyzed formulas reduced the risk of any allergic could be reintroduced into the diet after an oral food challenge outcomes including cow’s milk allergy and most concerningly [47]. The Choosing Wisely campaign has recommended noted a high degree of bias in positive outcome published against pre-emptive testing, noting “false or clinically irrele- studies to date [51]. It should also be noted that these formulas vant positive allergy tests for foods are frequent…IgE testing are cost-prohibitive and poorly tolerated in infancy. for specific foods must be driven by a history….” [48]. Pre- As a result, current evidence does not support the use of emptive screening to any food carries the risk of false-positive hydrolyzed formulas as a means of cow’s milk allergy preven- testing, which could inadvertently negate the possible benefits tion. As noted in the ASCIA guideline, “there is no consistent of early allergenic solid introduction. convincing evidence to support a protective role for partially As a result, pre-emptive testing to any allergen other than hydrolysed formulas…or extensively hydrolysed formulas for peanut, including tree nuts in a child with peanut allergy, is not the prevention of..food allergy” [52]. recommended. The one possible exception would be if a fam- ily would not feed tree nuts, or other allergens without testing (i.e., hesitancy despite counseling). To use tree nuts as an What Other Measures Can Be Useful example, in that situation one could consider either a graded in Preventing Food Allergy? oral challenge to tree nuts in the allergy office, or skin prick testing with consideration of an oral challenge if the results Several other measures—early skin moisturization [7–9], vi- were moderate or less. The goal would be early ingestion in tamin D supplementation [53, 54], and dietary diversity [55, the absence of pre-emptive testing, with testing only used in a 56]—have been proposed as other possible measures that may circumstance where feeding would not occur without it. have a role in allergy prevention. However, the literature to date on these measures is conflicting and no firm recommen- dation can be given at this time for any of these measures. Safety of Early Food Introduction in Infancy There were three initial randomized controlled trials on the use of early skin moisturization as a means of allergy preven- It should be noted that first ingestion of allergenic solids, tion in high-risk infants that were promising, noting decreased particularly in infancy, is safe. There has been no fatality on rates of eczema and in some cases food sensitization with first ingestion of a food in infancy. In the LEAP study, the rate early skin moisturization [57–59]. This practice, which is safe of adverse events was not different based on sensitization. At and easy to implement, would also fit with the theory of cu- baseline screening, only 7/319 infants failed the oral food taneous sensitization to foods. However, recent data suggests challenge and all 7 had mild reactions that did not require that this practice is not as effective as initially anticipated. For [3••]. In the EAT study, there were no cases of example, preliminary data from Preventing Atopic in the early introduction group [23••]. Population- and (PreventADALL) [60], presented based studies such as the HealthNuts have noted early inges- at the 2019 European Academy of Allergy and Clinical tion to be safe as well [40]. Immunology conference, noted no benefit to early and regular moisturization at least 3.5 days/week on the outcome of ecze- ma at a year of age. What About Use of Hydrolyzed Formula While studies have linked vitamin D exposure (or lack as a Means of Allergy Prevention? thereof) to the development of food allergy [53, 61, 62], the data on vitamin D insufficiency during pregnancy or perina- Previous guidelines recommended the use of hydrolyzed for- tally and its association with the development of food allergy mula in high-risk infants when mothers could not, or chose not remains mixed. While the HealthNuts data noted an associa- to, breastfeed, as a means of cow’s milk allergy and eczema tion between parental vitamin D insufficiency and risk of 60 Page 6 of 9 Curr Allergy Asthma Rep (2019) 19:60 peanut and/or egg allergy in childhood [54], a recent study of next month, they give egg once a week with no problems, but 1074 infants noted no association between vitamin D insuffi- have not had a chance to give tree nuts because of several viral ciency at birth and the risk of food allergy at a year of age [63]. colds recently. Due to the colds, 2½ weeks go by before they In addition, while increased diversity of diet has been get a chance to give egg again, but when they do, she has her shown in some observational studies to be associated with most severe reaction to date (, vomiting several times, reduced risk of food allergy, this approach has limitations face pale) requiring her Epipen Jr. and an emergency visit. including a lack of biologic plausibility, concerns that dietary Shortly after, sIgE testing returns at 15 kU/L to egg white, diversity may be prioritized over allergenic solid introduction, 0.74 kU/L to milk, and 2.61 kU/L to peanut, with cashew and no randomized studies to date [55, 56]. and walnut still negative. In the next few weeks, they try cashew but immediate hives result, while salmon on third exposure (they had been giving it once a week for 3 weeks) Putting It All Together: While Waiting results in vomiting 2 h after ingestion. Unlike her older broth- for Future Guidelines to Give More Specific er, wheat has been tolerated. You book them for a follow-up to Advice for Foods Other than Peanut, What repeat skin prick testing to tree nuts and fish, but also suggest Can We Do for High-Risk Families Who the milk ladder at home, plus put her on your very long Remain Hesitant and Confused? waiting list for egg and peanut oral . This case makes you question the utility of current guide- A case such as the following highlights how difficult it is for lines which focus solely on early introduction of peanut and practitioners in 2019 to give clear advice to parents for intro- cooked egg. In the absence of guidelines in your country ducing allergenic foods other than peanut and cooked egg. At clearly and firmly recommending early introduction of aller- 6 months of age, a girl with moderate/severe genic foods other than peanut and cooked egg, you decide that has been referred to you for consideration of allergy testing, if this family has a third child in the future, you will tell them given the 2½-year-old brother has anaphylactic wheat allergy that they “should” introduce “all” allergenic foods at around and the mother has anaphylactic . The brother has 6 months but not before 4 months. You remain very perplexed been on your waiting list for wheat oral immunotherapy for as to how to convince parents that they should continue to the past year, due to repeated anaphylaxis from accidental quickly introduce other allergenic foods even if their infant wheat exposures despite the family trying very hard to avoid experiences a reaction such as vomiting to peanut at 6 months, wheat. The referring physician had already discussed early use recognizing that parents who experience such an early reac- of emollients with the family when the infant was born. tion in their infant’s life may be hesitant to keep trying other Although you have a 1 year waiting list, you triage the infant allergenic foods and that your waiting list continues to grow to be seen at 7 months. because few colleagues offer infant oral challenges in your When the family arrives for their visit, the history confirms city. You also wonder how feasible it is in the real world for moderate/severe eczema since 3 months, treated with topical families like this to give a relatively long list of allergenic corticosteroids and topical antibiotics, for which she has been foods more often than once a week. followed by a pediatric dermatologist. At 4 months, she tried cow’s milk formula but they have been hesitant to re-try it because they feel it made her eczema worse. At 5 months, Conclusion they tried peanut butter on two occasions 2 weeks apart, both tolerated, but since the referral peanut butter was re-tried dur- While the most robust data to date exists for peanut, there are ing a viral cold and she vomited a couple of times, within 2 h emerging studies suggesting a beneficial effect to early intro- of ingestion. When you ask the parents whether they would duction of cooked egg, and cow’s milk as well. While the feel comfortable trying any allergenic foods again, they ex- literature is sparse for other allergens such as tree nuts, finned press extreme hesitancy and demand testing. Skin prick test- fish, and shellfish, the mechanism of sensitization is thought ing is positive for cow’s milk (8 × 4 mm) and peanut (7 × to be the same and no study to date has demonstrated a harm 4 mm) and negative to egg, cashew, walnut, wheat, fish, and with allergenic introduction in the 4–6 months of age window shrimp. You offer to bring her back for oral challenges to milk (nor has there been level 1 evidence of benefit to delay of such and peanut due to the history being not entirely convincing, allergens). It is important to note that this strategy is safe, and but the parents prefer re-trying at home to avoid your wait list, pre-emptive testing is not required prior to allergenic solid nowthattheyhaveanEpipenJr.Yousuggestintroducingthe introduction. foods that tested negative as soon as possible on a regular It must be emphasized that ongoing ingestion of allergens basis, such as 3 times a week. In the days that follow, re- is important and should be considered and asked about. trying peanut butter results in immediate hives and facial Moving forward, there remains many unanswered questions swelling and milk results in milder scattered hives. Over the including the role of measures such as early skin Curr Allergy Asthma Rep (2019) 19:60 Page 7 of 9 60 moisturization, dietary diversity, and vitamin D supplementa- 6.• Lack G. Update on risk factors for food allergy. J Allergy Clin – tion on allergy prevention. Further studies are required to as- Immunol. 2012;129:1187 97. Excellent review article on food allergy risk factors. sess the strengths and limitations of these approaches. 7. Irvine AD, McLean WHI, Leung DYM. Filaggrin mutations asso- A simpler message for future clinical practice guidelines is ciated with skin and allergic diseases. N Engl J Med. 2011;365: that parents should introduce high-risk infants to all allergenic 1315–27. solids early “at around 6 months but not before 4 months,” as 8. van den Oord RAHM, Sheikh A. Filaggrin gene defects and risk of developing allergic sensitisation and allergic disorders: systematic it is unlikely for clinical trials like LEAP and PETIT to be review and meta-analysis. 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J Allergy Clin Immunol. 2010;126:807–13. Conflict of Interest EMA received an unrestricted educational grant 12.•• Natsume O, Kabashima S, Nakazato J, Yamamoto-Hanada K, from Novartis and is a member of the scientific advisory board for Narita M, Kondo M, et al. Two-step egg introduction for prevention Food Allergy Canada. ESC has received research support from DBV of egg allergy in high-risk infants with eczema (PETIT): a Technologies, has been a member of advisory boards for Pfizer, randomised, double-blind, placebo-controlled trial. Lancet Pediapharm, Leo Pharma, and Kaleo, is a member of the scientific advi- (London, England). 2017;389:276–86. Randomized controlled sory board for Food Allergy Canada, and was an expert panel and coor- trial supporting early cooked egg introduction as a means of dinating committee member of the National Institute of Allergy and allergy prevention. Infectious Diseases (NIAID)-sponsored Guidelines for Peanut Allergy 13. 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